Method of producing alpha-brominated keto steroid compounds



Oct. 23, I956 G. VNOMINE ET AL 2,768,189

METHOD OF PRODUCINGd-BROMINATED KETO STEROID COMPOUNDS Filed June 11, 1953 c gzo c-cn c n o crcu "F v co aura- C H2O c-CH3 0 co 3'3 0 ---OH flltii l.

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WMWMM mmar WTTORNEYS United States Patent METHOD OF PRODUCING u-BROIVIINATED KETO STEROID COB [POUNDS Grard Nomine, Noisy-le-Sec, and Julien Warnant, Paris, France, assignors to Les Laboratoires Frangais de Chimiotherapie, Paris, France, a corporation of France Application June 11, 1953, Serial No. 360,878 Claims priority, application France May 20, 1953 10 Claims. (Cl. 260-3973) The present invention relates to an improved method of producing keto steroid compounds being brominated in Ot-POSitlC-Il to said keto group.

Among the keto steroid compounds used in therapy, there are a number of valuable compounds which possess a double bond in anti-position to their keto group in 3- position in ring A. Such compounds are, for instance, progesterone, cortisone, desoxycorticosterone, testosterone and others. The introduction of such an a,,6-unsaturated ketonic group is usually the last step in the synthesis of such compounds, i. e., takes place at a time when the yield achieved thereby is of particular importance.

In case the intermediate product preceding this last synthesis step is derived, for instance, from cholesterol and contains a double bond in 5,6-position and a secondary alcohol group in 3-position, the elegleant method of 0ppenauer, as described, for instance, in French Patent No. 827,623, is used for establishing the keto function in 3- position and at the same time for causing migration of the double bond from the 5,6-position to the 4,5-position. Starting materials of this type are, for instance, 3/8- hydroxy A pregnene-ZO-one, 17mono-acyl-A -a.ndrostene 3 3,175 diols, SB-Hydroxy-Zl-acetoxy-M-pregnene- 20-one and others.

However, when the preceding intermediate is a saturated compound, for instance, a compound derived from bile acids in which the rings A and B are of cis-config-uration, or a so-called allo-compound as obtained by hydrogenation of sterols in which the rings A and B are of trans-configuration, other methods are used to transform such compounds into 0a,,B-HI1S3tL1I316d ketones. In this case the ordinarily used process consists in first producing the monoor di-brominated intermediate compounds in which the bromine atom or atoms are in a-position to the keto groups.

Such brominated compounds are then subjected to the action of a tertiary base to split ofl hydrogen bromide therefrom and to introduce a double bond in 4,5-position in compounds of the normal series and in 1,2-position in compounds of the allo series. Hydrogen bromide may also be split off by the intermediate formation of a hydrazone.

In order to transform androgenic steroid compounds into estrogenic compounds, it is necessary to aromatize ring A and, at the same time, to eliminate the methyl group in lo-position. To successfully eifect such aromatization reaction by cracking, first a compound of a high degree of unsaturation in ring A must be produced. Such a compound is obtained by preparing, as intermediate compounds, a,a-dibrominated 3-keto steroid compounds which are then converted into the corresponding dienones. These compounds having two double bonds and a keto group in ring A are compounds of such a high degree of unsaturation that, on cracking, they yield an aromatic ring A.

Until recently the above described bromination reactions were effected by means of bromine. It was found ICC and B in cis-configuration to each other, yield predomi nantly the 4-brominated derivative. The reaction product, however, is always contaminated by the Z-brominated derivative and by varying quantities of the 2,4-di brominated derivative.

In contrast hereto, 3-keto steroids of the allo-s'eries hav ing rings A and B in trans-configuration to each other yield with bromine Z-brominated and 2,2-dib'rominated derivatives. Said 2,2-dibrominated derivative can subsequently be rearranged, by the action of hydrobromic acid, to the corresponding 2,4-dibrominated derivative. This rearrangement has been successfully used by Rosenkranz et al., Journal of the American Chemical Society, vol. 72, page 4077 (1950), for the introduction of a double bond into 4,5-position of steroid compounds of the allo-series. For this purpose the 2,4-dibromo derivative is terated with sodium iodide thereby substituting bromine in 2-position by iodine. Collidine eliminates from said 2-iodo-4-bromo compound one mol of hydrobromic acid, thus producing a double bond in 4,5-position. At the same time the iodine atom in 2-position is replaced by a hydrogen atom, thereby producing a keto steroid having a double bond in 4,5-position.

This reaction is also employed in the industrial estrone synthesis according to Inhofiens process. Starting material is 17 8-hydroXy androstanone-3, an ester of which is reacted with bromine to form the corresponding 2,2-dibrominated compound. Said compound is then converted into the corresponding 2,4-dibrominated compound which, on splitting ofi hydrogen bromide, forms the intermediate product for the aromatization process,

' namely the A -dienone-3-compound.

that 3-keto steroids of the normal series having rings A Bromination of keto steroids in a-position is furthermore of great interest in the synthesis of certain adrenocortical hormones, such as cortisone, corticoster'one, 17- hydroxy corticosterone and others. This method is, in fact, successfully employed in the conversion of desox'ycholic acid having a hydroxyl group in 12-position into an acid or corresponding ester having a keto group in ll-position. Such a keto group in ll-position represents a characteristic feature of cortisone. By reducing said keto group, compounds are obtained which possess in ll-position the hydroxyl group which is characteristic for corticosterone and 17-hydroxy corticosterone. In carrying out the process of converting desoxycholic acid, the hydroxyl group in 3-position of said acid is protected, for instance, by esterification, the secondary alcohol group in 12-position is oxidized to the keto group, the compound is brominated whereby one bromine atom is introduced in a-position to the keto group, i. e. in'll-position, and the halogen is saponiiied to the corresponding ll-hydroxy-lZ-keto compound. Said compound is readily isomerized to the corresponding ll-keto-lZ-hydroxy compound. When removing and exchanging the hydroxyl group in 12-positi0n by hydrogen, there remains the keto group in ll-position which is characteristic for cortisone.

The yields achieved by direct bromination according to the known methods, however, vary considerably and are often quite low. Depending upon the constitution of the keto steroid used as starting material, reaction of other positions of said compounds with bromine may oc cur. Attempts have been made to overcome these difiiculties by varying the amount of bromine to be reacted Such variations, however, did not improve the yield. Mattox and Kendall, Journal of Biological Chemistry, vol. 185, page 598 (1950),. for instance, obtained on bromination of t-hYdIOXY-21-3C31IOXY pregnane-3,ll,20- trione, a mixture of 4-bromiuated and 2-brominated derivatives in the ratio of 3 to l.

It is one object of this invention to provide a method of producing oz-brominated keto steroid compounds which method does not have the disadvantages and drawbacks of the bromination methods used heretofore and in which halogenation is coupled with dehydrogenation of an oxidizable alcohol. The best results are obtained with N- bromo succinimide, but other N-bromo imides, N-bromo amides, or N-bromo hydantoines may also be used.

" Another object of this invention consists in providing a method for the production of 2,4-dibromo androstane-3- one compounds, by bromination of androstanone-3 compounds or by dibromination and oxidation of androstanol- 3-compounds. The resulting 2,4-dibromo androstane-3- {one compounds are important intermediates in the process of converting androgenic steroid compounds into estrogenic steroid compounds.

A further object of this invention consists in providing a method for the production of 2,4-dibromo androstane- 3-one and allo pregnane-3-one compounds by brominating 3-keto or 3-hydroxy androstane and allo pregnane (compounds of the allo-series). Said method greatly reduces the number of steps required to produce the corresponding 3-keto A androstadiene and pregnadiene compounds from such starting materials since it permits direct introduction of bromine in 2,4-position.

Still another object of this invention consists in providing a method for producing ll-brominated l2-keto steroid compounds, starting from 12-keto or 12-hydroxy steroid compounds, such as 3u-hYdIOXY-12-k6t0 cholanic acid or desoxycholic acid. The resulting ll-brominated l2-keto steroid compound is a valuable intermediate product in the production of ll-keto or hydroxy steroid compounds from 12-hydroxy steroid compounds and greatly facilitates the conversion of bile acids into cortisone and similar compounds with an oxygen containing substituent in ll-position.

Other objects of this invention and some of the ad vantageous features thereof will become apparent as the description of the invention proceeds.

In principle, this invention consists in the action of two mols of N-bromo succinimide upon one mol of a keto steroid in the presence of an oxidizable alcohol according to the following formulas and equations. In these formulas and equations S represents the radical ([lHaC0- CHzCO A. Oxidation reaction:

R2 in these formulas is an alkyl or an aralkyl residue and R3 hydrogen or an alkyl residue.

The above given general equation may be resolved into the following equations:

B. Bromination reaction:

Keto steroid Bromlnated keto steroid It is evident that when working according to this invention, bromo succinimide is hydrolized whereby two mols 0f hypobromous acid are set free. One mol of said hypobromous acid oxidizes the oxidizable alcohol, thereby setting free one mol of hydrobromic acid while the other mol thereof reacts with the hydrobromic acid formed and yields bromine. The bromine set free in this manner reacts under conditions which are different from those encountered when adding bromine directly to the reaction mixture.

The fact that the reaction starts with a hydrolysis can be proved by completely suppressing said reaction by the addition of a small amount of acetic anhydride to the reaction mixture. It is, therefore, advisable to always add a small amount of Water to the reaction mixture in order to facilitate hydrolysis.

Reaction A.3 above which results in the formation of bromine proves the presence of hydrobromic acid produced by reaction A.2 above. Said reaction A2 is an oxidation reaction in the proper sense of the word. Apparently bromination with N-bromo succinimide cannot take place if it is not preceded by such an oxidation. One may, of course, supply hydrobromic acid to the reaction mixture instead of liberating said acid by means of such an oxidation reaction.

The reaction with bromo succinimide is preferably carried out at about 60 C. whereby best results are achieved. One may, however, also work at much lower or higher temperatures. In contrast to usual bromination reactions, by means of N-bromo succinimide whereby the reaction mixture is exposed to strong light, it is possible to operate, according to the process of this invention, in the complete absense of light, i. e., in the dark. The oxidizable alcohol may be any primary or secondard alcohol which can be readily oxidized to an aldehyde or ketone, respectively. One may employ an equimolecular quantity of said alcohol or even a slight excess thereof, preferably not exceeding 15%.

It is, of course, understood that, in order to effect dibromination, 4 mols of N-bromo succinimide and 2 mols of the oxidizable alcohol must be used. The reaction is best carried out in the presence of tertiary butyl alcohol. One may, of course, use other solvents such as chloroform, methanol, acetic acid or the like which are capable of dissolving the reaction compounds without themselves being affected by bromo succinimide.

A great advantage of the new process according to this invention consists in its greater selectivity and in the higher yields obtained in comparison with the known processes using bromine as reactant. For instance, 17ahydroxy-Zl-acetoxy pregnane-3,ll,20-trione yields the corresponding 4-bromo dcrivativethe last before the last intermediate product in the synthesis of cortisoneacetate with a yield of 70% to 75% whereby its rotatory power [061D is +104.

When starting with pregnane-3,20-dione, 4-bromo pregnane-3,20-dione is obtained which is readily convertible into progesterone.

In contrast to all the processes known heretofore, one obtains directly the 2,4-dibromo derivatives when starting with allo-compounds and proceeding according to this invention. This surprising reaction simplifies considerably, for instance, the conversion of androgenic steroid compounds into estrogenic ones and thus represents one of the most important advances in this art. It provides a markedly improved way of making estrone synthetically by using as starting materials a 17-ester of androstandiol-3,17. Heretofore, it was only possible to obtain the 2,2-dibromo derivative of androstanolone which subsequently had to be converted into the 2,4-dibromo derivative. When reacting N-bromo succinimide according to the process of this invention with androstanc- 3B-ol-l7-one, the 2,4-dibromo androstane-3,l7-dione is directly obtained,

The above given reaction formulas and equations show that an oxidizable alcohol is necessary for the reaction to take place. In general, a suitable oxidizable alcohol is added to the reaction mixture and reacts as external reactant. One may, however, proceed in such a manner that the steroid molecule itself supplies said alcoholic function. For this purpose a steroid compound containing an oxidizable alcohol group is used as reactant. Such steroid alcohol is oxidized to the corresponding ketone before bromination takes place .or at the same time therewith. However, When only mono-bromination of a compound containing a hydroxyl group is desired, it is of advantage to add a certain amount of another oxidizable alcohol as external reactant to the reaction mixture in order to supply the necessary excess of such oxidizable alcohol corresponding to the excess of N-bromo succinimideused, When dibrominating a hydroxy steroid, said hydroxy steroid may be treated with 4 mols of N- bromo succin-irnide in the presence of only one mol of a simple oxidizable alcohol because the hydroxyl group of the steroid compound supplies the second mol of the required oxidizable alcohol. Thereby the dibromo derivative of the corresponding keto steroid is formed.

The process according to this invention is superior to any known industrial processes of this type on account of its great simplicity. Ordinarily, it is suflicient to mix the reaction products in the presence of a solvent and a small amount of water, to increase the temperature to about 60 C., and to precipitate the reaction product by pouring the reaction mixture into water. The resulting brominated product is filtered .off, dried, and purified by recrystallization.

The following examples serve to illustrate the invention without, however, limiting the same thereto. The melting points given were determined in the Maquenne block, the rotatory power, if not stated otherwise, in acetone solution in a concentration of 1%.

Example 1.Br0minatf0n of l7u-hydroxy-2l-acetoxy pregnane-3 ,1 1 ,20-tr'z'0ne (Fig. 1 of the attached drawing) A mixture of:

1.0 g. of 17a-hydroXy-21-acetoxy pregnane-3,11,20-

trione,

0.98 g. (2.2 mol) of bromo succinimide,

0.3 cc. (1.12 mol) of benzyl alcohol,

cc. of tertiary butyl alcohol, and

0.15 cc. of water g. of the pure brominated product crystallize which melt at 257 C. Yield: 73%. Rotatory power [al z +104". On analysis 16.8% of bromine were found (calculated: 16.5%). This product, on dehydrobromination, yields cortisone acetate. 7 1

Example 2.Bromination of pregmme-3,20-di0ne (Fig. 2 of the attached drawing) A mixture of:

2.8 g. of pregnandione-3,20 (M. P., 120 C.), 28 cc. of tertiary butyl alcohol,

1.05 g. (1.1 mols) of benzyl alcohol,

0.5 cc. of distilled water, and

3.47 g. (2.2 mols) of N-bromo succinirnide is heated to C. while stirring. After heating the mixture for 5 minutes the solution acquires a strongly reddish color. Heating is continued. A short time thereafter decolorization starts and the solution becomes colorless after about 50 minutes. The reaction mixture is cooled to room temperature and is poured into 140 cc. of water containing 3 cc. of a sodium bisulfite solution of 35 Baum. The precipitate is filtered olf, washed with water and 60% methanol, and dried at 60 C. 3.35 g. of the crude bromination product, corresponding to a yield of 96%, melting at about 165 C., are obtained. Said crude product is triturated, while heating, with 3 times its volume of acetone, cooled with ice, filtered, and washed with as little as possible of ice-cool acetone. After drying the product at 60 C., 1.92 g, of a first crop of 4-bromo pregnandione-3,2O are obtained. Melting point: 202- 204 C.; rotatory power lai +i166i2 (1% in chloroform solution). Yield: About 55%.

Analysis: C21H31O2B1':

Calculated 63.78% C, 7.90% H, 20.21% Br Found 63.60% C, 7.90% H, 20.30% Br On dehydrobromination, progesterone is obtained therefrom.

Example 3.Br0m0-0xidati0n of 3a,17u-dihydr0xy-21- acetoxy pregnane-I 1 ,20-di0ne (Fig. 3 of the attached drawing) A mixture of:

50.0 g. of 3a,17a-dihydroxy-21-acetoxy pregnane-ILZO- dione,

96.3 g. (4.4 mol) of N-bromo succinimide,

9.5 cc. (1 mol) of isopropyl alcohol,

8.0 cc. of water, and

500 cc. of tertiary butyl alcohol are heated to 60 C. After 20 minutes, the reaction mixture does not show any reaction with potassium iodide-starch paper. The mixture is poured into 2.5 liters of ice-Water, the precipitate is filtered, washed with water, and dried. 62.7 g. of a crude product containing 19.819.9% of bromine, are obtained. The theoretical amount of bromine is 16.5% and the higher bromine content of the crude reaction product indicates that a small amount of the 4,21-dibrominated compound is formed together with the 4-monobrominated derivative. In order to completely convert said crude product into the 4-monobrominated derivative, the bromine in 21- position is removed by means of sodium iodide in the following manner:

5 g. of said crude product are dissolved in 75 cc. of acetone. Said solution is added to a solution of 5 g. of sodium iodide in 5 cc. of Water. The mixture is allowed to stand at 20 C. for one hour. 5 cc. of pure formic acid are then added and the mixture is again allowed to stand at 20 C. for one hour. It is poured into 750 cc. of water and ice containing 5 cc. of a commercial sodium bisulfite solution. The precipitate is filtered, washed, and dried. 4.6 g. of a product are obtained which contains 16.8% of bromine (the theoretical bromine content is 16.5%). Its rotatory power is [a] :+93.3.

On purification with aqueous acetone, a product is obtained which is identical with the product produced according to Example 1. The yield is 3.7 g., corresponding to 75% of the starting material. The pure 4-bromo- 17oz-hYdl0XY-21-3C61OXY pregnane-3,11,20-trione exhibits a rotatory power of [a] Z+1O4- and contains 16.4% of bromine.

Example 4.--2.4-dibrominati0n and oxidation of 30:,17oz dihydroxy pregnane-I 1,20-di0ne (Fig. 4 of the attached drawing) A mixture of:

1.0 g. of 3u,17a-hydroxy pregnandione-11,20, 2.25 g. (4.4 mol) of N-bromo succinimide, 0.33 cc. 1.1 mol) of benzylalcohol,

0.15 cc. of water, and

10 cc. of glacial acetic acid 7 aqueous acetone 0.775 g. of the pure product melting at 244-246 C. and having a rotatory power of [a] :+62+ 2 (1% in acetonic solution) are obtained.

Analysis:

Calculated 50.0% C, 5.6% H, 12.7% 0, 31.7% Br Found 49.8% C, 5.6% H, 12.7% 0, 31.2% Br On treating this compound with zinc dust and acetic acid, the two bromine atoms are exchanged by hydrogen atoms and the 17a-hydroxy pregnane-3,l1,20-trione is obtained. It melts, after recrystallization from aqueous acetone, at 205 C.

Analysis:

Calculated 72.80% C, 8.73% H, Br Found 72.80% C, 8.80% H, absent Example 5.2,4-dibr0minati0n and oxidation of the 17-benz0ate of androstane-3flJ7fl-diol (Fig. 5 of the attached drawing) A mixture of:

5.0 g. of the 17-benzoate of androstane-3fi,l7fl-diol, 50 cc. of acetic acid, 1.45 g. (1.1 mols) of benzyl alcohol,

0.75 cc. of water, and

9.9 g. (4.4 mols) of N-bromo succinimide is heated in a 100 cc. flask to 60 C. After 25 minutes, the reaction mixture does not show any reaction with moist potassium iodide-starch paper. The mixture is poured into 250 cc. of ice-water. The precipitate is filtered oif, washed with water and then with methanol, and dried. 6 g. of a product are obtained which melts first at 192 C. and subsequently at 207 C. Rotatory power [a] Z+45. Yield: 86%.

Purification is effected by digesting with 12 cc. of methanol while boiling under reflux. 5.55 g. of a white product are obtained which, on recrystallization, melt first at 204 C. and subsequently at 215 C. This compound does not give any depression of the melting point when mixed with a sample of the benzoate of 2,4-dibromo androstanolone.

On splitting off hydrobromic acid by means of collidine and saponifying, A -dehydrotestosterone melting at 170 C. and having a rotatory power of [a] :+24+2 (1% in chloroform), is obtained.

Analysis:

Calculated 79.68% C, 9.15% H Found 79.80% C, 9.10% H Ultraviolet adsorption in ethanol solution: A, 2450- 2470; A max., 3000; 6 max., 14,750; e, 206.

This product is an important starting material in the synthesis of estradiol. Inhotfeu (Berichte der deutschen chemischen Gesellschaft, vol. 76, 1943, page 239) prepared the same compound by brominating the same starting material in 2,2-position and converting the 2,2-dibromo compound into the 2,4-dibromo derivative without indicating the yield obtained thereby.

Example 6.2,4-dibr0mination and oxidation of 3 hydroxy androstane-17-0ne (Fig. 6 of the attached drawing) A mixture of:

5.0 g. of 3B-hydroxy androstanc-17-one (isoandrosterone),

50 cc. of aceticacid containing 1.5% of water,

1.9 cc. 1.1 mols) of benzyl alcohol, and

13.5 g. (4.4 mols) of N-brorno succinimide is heated to 60 C. After 30 minutes the reaction mixture does not .show any reaction with moist potassium ture.;

iodide-starch paper. -The mixture is poured, While stirring, into 500 cc. of ice-water containing 5 cc. of sodium bisulfite' solution, and stirring is continued at 0 C. for one hour. The precipitate is filtered, washed until the wash water is neutral, and dried. 8 g. of a crude product are obtained. The dibromo derivative is then washed three times with absolute methanol, each time with 10 cc., and three times with ether, each time also with 10 cc. On drying, 5.3 g. of 2,4-dibromo androstandione melting at 253 C. are obtained, corresponding to a yield of about 69%. Said product is suflicicntly pure for splitting oif hydrobromic acid to form A -androstadiene 3,17-dione. In contrast to the methods described in the literature, not only the reaction time but also the number of reaction steps in the synthesis of estrone are considerably reduced. The present example, thus, serves to illustrate more particularly the specificity and the advantages of the process according to this invention.

By trituration with acetone, an analytically pure 2,4- dibromo androstandione is obtained in the amount of 4.25 g. Melting point (in the Maquenne block): 282 C.; rotatory power [on] I+39.5' 'l.5 (c: 1% in chloroform solution).

Analysis: For C19H26B1'2O2:

Calculated 51.00% C, 5.80% H, 35.50% Br Found 51.14% C, 5.87% H, 35.82% Br It is understood that, in case a steroid compound is used as starting material having several keto and/or hydroxyl groups in its molecule, bromination primarily takes place in wposition to the 3-keto or S-hydroxyl group. To efiect bromination at other places of the molecule, requires protection of the keto or hydroxyl group in 3-position, for instance, by esterification or by any other suitable means.

We claim:

1. In a process of producing 2,4-dibromo-17a-hydroxy pregnane-3,11,20-trione, the steps comprising heating a mixture of 1 mol equivalent of 3a,17oc-dihydroxy pregnane-11,20-dione, about 4 mol equivalents of N-bromo succinimide, and about 1 mol equivalent of benzyl alcohol, in about 98.5% acetic acid to about 60 C. until the reaction mixture does not react with potassium iodide starch paper, and isolating the resulting 2,4-dibromo-17ahydroxy pregnane-3,11,20-trione from the reaction mixture.

2. In a process of producing 2,4-dibrorno-17-benzoyloxy androstane-3-one, the steps comprising heating a mixture of 1 mol equivalent of the 17-benzoate of androstane-3B,17;8-diol, about 4 mol equivalents of N-bromo succinimide, and about 1 mol equivalent of benzyl alcohol in about 98.5 acetic acid to about 60 C. until the reaction mixture does not react with potassium iodidestarch paper, and isolating the resulting 2,4-dibromo androstanol-17-one-3 from the reaction mixture.

3. In a process of producing 2,4-dibromo androstane- 3,17-dione, the steps comprising heating a mixture of 1 mol equivalent of 3fl-hydroxy. androstane-l7-one, about 4 mol equivalents of N-bromo succinimide, and about 1 mol equivalent of benzyl alcohol in about 98.5 acetic acid to about 60 C. until the reaction mixture does not react with potassium iodide-starch paper, and isolating the resulting 2,4-dibromo androstane-3,17-dione from the reaction mixture.

4. In a process of producing 4-bromo-17a-hydroxy- 21-acetoxy pregnane-3,l1,20-trione, the steps comprising heating a mixture of 1 mol equivalent of 3a,17a-dihydroxy-21-acetoxy pregnane-11,20-dione, about 4 mol equivalents of N-bromo succinimide, and about 1 mol equivalent of isopropyl alcohol in tertiary butyl alcohol containing water, to about 60 C. until the reaction mixture does not react with potassium iodide-starch paper, and isolating the resulting 4bromo-17u-hydroxy-21' acetoxy-pregnane-3 ,1 1,20-trione from the reaction mixwherein R2 is a substituent selected from the group consisting of the keto group and hydrogen; R3 is a substituent selected from the group consisting of the secondary hydroxyl group, the secondary hydroxyl group acylated by a lower alkanoic acid, the secondary hydroxyl group acylated by benzoic acid, the aceto group CO.CH3

the a-hydroxy aceto group CO.CH2OH, and the alower alkanoyloxy aceto group CO.CH2OAcyl, and the oz-bCIlZGYlOXY aceto group CO.CH2O benzoyl; and R4 is a substituent selected from the group consisting of hydrogen and the tertiary hydroxyl group, and R3 and R4 together being the keto group, the steps comprising heating a mixture of N-brorno succinimide and a steroid compound of the formula wherein R1 is a substituent selected from the group consisting of the keto group and the secondary hydroxyl group, while R2, R3 and R are the same substituents as indicated above, in the presence of water and an 5 oxidizable alcohol selected from the group consisting of benzyl alcohol and isopropyl alcohol, to a temperature between about 50 C. and about 70 C., the proportion of steroid compound, N-bromo succinimide, and oxidizable alcohol in said mixture, calculated for each bromine atom introduced in CC-POSitiOH to the keto group, being one mol of steroid compound to about 2 mols of N-bromo succinimide to at least about 1 mol of oxidizable alcohol, and separating the resulting a-brominated kcto steroid compound from the reaction mixture.

7. The process of producing u-br-ominated 3-keto steroid compounds according to claim 6, wherein bromination is carried out in the presence of an organic solvent for the steroid compound as well as for N-bromo succinirnide, said solvent not being affected by N-bromo succinimide.

8. The process of producing a-brominated 3-keto steroid compounds according to claim 7, wherein the organic solvent is tertiary butyl alcohol.

9. The process of producing a-brominated 3-keto steroid compounds according to claim 7, wherein the organic solvent is crystallizable acetic acid.

10. 2,4-dibromo-17a-hydroxy pregnane-3,11,20-trione.

References Cited in the file of this patent 5 OTHER REFERENCES Djerassi: Chem. Reviews, 43, pp. 293-294, 302 and 312 (1948). 

1. IN A PROCESS OF PRODUCING 2,4-DIBROMO-17A-HYDROXY PREGNANE-3,11,20-TRIONE, THE STEPS COMPRISING HEATING A MIXTURE OF 1 MOL EQUIVALENT OF 3A, 17A-DIHYDROXY PREGNANE-11,20-DIONE, ABOUT 4 MOL EQUIVALENTS OF N-BROMOSUCCINIMIDE, AND ABOUT 1 MOL EQUIVALENT OF BENZYL ALCOHOL, IN ABOUT 98.5% ACETIC ACID TO ABOUT 60* C. UNTIL THE REACTION MIXTURE DOES NOT REACT WITH POTASSIUM IODIDESTARCH PAPER AND ISOLATING THE RESULTING 2,4,-DIBROMO-17AHYDROXY PREGNANE-3,11-20-TRIONE FROM THE REACTION MIXTURE. 